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The stem cell population of the human colon crypt: analysis via methylation patterns.

Nicolas P, Kim KM, Shibata D, Tavaré S - PLoS Comput. Biol. (2007)

Bottom Line: Previous analyses were based on forward simulation of the cell content of the whole crypt and subsequent comparisons between simulated and experimental data using a few statistics as a proxy to summarize the data.Results support a scenario where the colon crypt is maintained by a high number of stem cells; the posterior indicates a number greater than eight and the posterior mode is between 15 and 20.The results also provide further evidence for synergistic effects in the methylation/demethylation process that could for the first time be quantitatively assessed through their long-term consequences such as the coexistence of hypermethylated and hypomethylated patterns in the same colon crypt.

View Article: PubMed Central - PubMed

Affiliation: Unité Mathématique Informatique et Génome UR1077, Institut National de la Recherche Agronomique, Jouy-en-Josas, France. pierre.nicolas@jouy.inra.fr

ABSTRACT
The analysis of methylation patterns is a promising approach to investigate the genealogy of cell populations in an organism. In a stem cell-niche scenario, sampled methylation patterns are the stochastic outcome of a complex interplay between niche structural features such as the number of stem cells within a niche and the niche succession time, the methylation/demethylation process, and the randomness due to sampling. As a consequence, methylation pattern studies can reveal niche characteristics but also require appropriate statistical methods. The analysis of methylation patterns sampled from colon crypts is a prototype of such a study. Previous analyses were based on forward simulation of the cell content of the whole crypt and subsequent comparisons between simulated and experimental data using a few statistics as a proxy to summarize the data. In this paper we develop a more powerful method to analyze these data based on coalescent modelling and Bayesian inference. Results support a scenario where the colon crypt is maintained by a high number of stem cells; the posterior indicates a number greater than eight and the posterior mode is between 15 and 20. The results also provide further evidence for synergistic effects in the methylation/demethylation process that could for the first time be quantitatively assessed through their long-term consequences such as the coexistence of hypermethylated and hypomethylated patterns in the same colon crypt.

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Modelling Differentiation Lineages(Upper panel) Shows the genealogical structure of a crypt subpopulation made of the progeny of the same stem cell. Differentiation process spans more than five rounds of cell divisions (g = 5), and differentiated cells are removed from the crypt when a new generation of differentiated cells arrives. Levels of gray ranging from white for the stem cell lineage to black for the differentiated cells indicate the different differentiation stages.(Lower panel) Illustrates the star-likeness of the genealogy of three cells randomly sampled from the progeny of the same stem cell. The lines of descent of these three cells are highlighted in black.
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pcbi-0030028-g002: Modelling Differentiation Lineages(Upper panel) Shows the genealogical structure of a crypt subpopulation made of the progeny of the same stem cell. Differentiation process spans more than five rounds of cell divisions (g = 5), and differentiated cells are removed from the crypt when a new generation of differentiated cells arrives. Levels of gray ranging from white for the stem cell lineage to black for the differentiated cells indicate the different differentiation stages.(Lower panel) Illustrates the star-likeness of the genealogy of three cells randomly sampled from the progeny of the same stem cell. The lines of descent of these three cells are highlighted in black.

Mentions: Sampled methylation patterns are related to those found in the stem cell lineages through three parameters, g, α, and ɛ. The parameter g can be interpreted as the number of cell cycles of the cell differentiation process. It describes the shape of the genealogy of cells sampled from the progeny of the same stem cell (illustrated in Figure 2). Higher values of g correspond to genealogies that tend to have longer terminal branches (and so are more star-like). The parameter α reflects the ratio between the amount of methylation and demethylation in a cell lineage during the cell differentiation process and in a stem cell lineage in time τ. More precisely, α = η/ν, where η is expressed in terms of the expected number of events in a single lineage during the few cell divisions of the differentiation process. The parameter ɛ corresponds to the rate of sequencing error per site per sequence.


The stem cell population of the human colon crypt: analysis via methylation patterns.

Nicolas P, Kim KM, Shibata D, Tavaré S - PLoS Comput. Biol. (2007)

Modelling Differentiation Lineages(Upper panel) Shows the genealogical structure of a crypt subpopulation made of the progeny of the same stem cell. Differentiation process spans more than five rounds of cell divisions (g = 5), and differentiated cells are removed from the crypt when a new generation of differentiated cells arrives. Levels of gray ranging from white for the stem cell lineage to black for the differentiated cells indicate the different differentiation stages.(Lower panel) Illustrates the star-likeness of the genealogy of three cells randomly sampled from the progeny of the same stem cell. The lines of descent of these three cells are highlighted in black.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1808490&req=5

pcbi-0030028-g002: Modelling Differentiation Lineages(Upper panel) Shows the genealogical structure of a crypt subpopulation made of the progeny of the same stem cell. Differentiation process spans more than five rounds of cell divisions (g = 5), and differentiated cells are removed from the crypt when a new generation of differentiated cells arrives. Levels of gray ranging from white for the stem cell lineage to black for the differentiated cells indicate the different differentiation stages.(Lower panel) Illustrates the star-likeness of the genealogy of three cells randomly sampled from the progeny of the same stem cell. The lines of descent of these three cells are highlighted in black.
Mentions: Sampled methylation patterns are related to those found in the stem cell lineages through three parameters, g, α, and ɛ. The parameter g can be interpreted as the number of cell cycles of the cell differentiation process. It describes the shape of the genealogy of cells sampled from the progeny of the same stem cell (illustrated in Figure 2). Higher values of g correspond to genealogies that tend to have longer terminal branches (and so are more star-like). The parameter α reflects the ratio between the amount of methylation and demethylation in a cell lineage during the cell differentiation process and in a stem cell lineage in time τ. More precisely, α = η/ν, where η is expressed in terms of the expected number of events in a single lineage during the few cell divisions of the differentiation process. The parameter ɛ corresponds to the rate of sequencing error per site per sequence.

Bottom Line: Previous analyses were based on forward simulation of the cell content of the whole crypt and subsequent comparisons between simulated and experimental data using a few statistics as a proxy to summarize the data.Results support a scenario where the colon crypt is maintained by a high number of stem cells; the posterior indicates a number greater than eight and the posterior mode is between 15 and 20.The results also provide further evidence for synergistic effects in the methylation/demethylation process that could for the first time be quantitatively assessed through their long-term consequences such as the coexistence of hypermethylated and hypomethylated patterns in the same colon crypt.

View Article: PubMed Central - PubMed

Affiliation: Unité Mathématique Informatique et Génome UR1077, Institut National de la Recherche Agronomique, Jouy-en-Josas, France. pierre.nicolas@jouy.inra.fr

ABSTRACT
The analysis of methylation patterns is a promising approach to investigate the genealogy of cell populations in an organism. In a stem cell-niche scenario, sampled methylation patterns are the stochastic outcome of a complex interplay between niche structural features such as the number of stem cells within a niche and the niche succession time, the methylation/demethylation process, and the randomness due to sampling. As a consequence, methylation pattern studies can reveal niche characteristics but also require appropriate statistical methods. The analysis of methylation patterns sampled from colon crypts is a prototype of such a study. Previous analyses were based on forward simulation of the cell content of the whole crypt and subsequent comparisons between simulated and experimental data using a few statistics as a proxy to summarize the data. In this paper we develop a more powerful method to analyze these data based on coalescent modelling and Bayesian inference. Results support a scenario where the colon crypt is maintained by a high number of stem cells; the posterior indicates a number greater than eight and the posterior mode is between 15 and 20. The results also provide further evidence for synergistic effects in the methylation/demethylation process that could for the first time be quantitatively assessed through their long-term consequences such as the coexistence of hypermethylated and hypomethylated patterns in the same colon crypt.

Show MeSH